There are an estimated 5,000 genetic diseases in man, and the etiology of the vast majority of these is unknown. Without knowledge of the physiological basis for a particular disease, other approaches are necessary in order to understand the genetic defect responsible for any clinically abnormal phenotype. In the past decade or so, tremendous advances have been made in understanding the human genome and in identifying disease loci. For example, loci for the following diseases have recently been cloned: cystic fibrosis, fragile X syndrome, Huntington's disease, amyotropiclateral sclerosis, Duchenne muscular dystrophy, myotonic dystrophy, von Hippel-Lindau (VHL) syndrome, and others. Many of these success stories have involved human genetic maps and the process of reverse genetics. This refers to utilizing linkage analysis to examine the co-inheritance of polymorphic markers in families with disease phenotypes. Previously mapped and newly isolated genes from the appropriate region may then be examined as candidates for a particular disease gene. Our gene mapping project is a collaborative multidisciplinary activity that assigns human genes and markers to both physical and linkage maps. These assignments serve not only as critical information regarding gene characterization, but also represent mapped loci as candidate disease genes. In the past year, our group has participated in the identification of two important disease genes: those for VHL syndrome and X-linked severe combined immunodeficiency syndrome.